What is the best approach to manage elevated cortisol levels in a patient with a history of Cushing's syndrome, obesity, or other conditions that may contribute to hypercortisolism?

Management of Elevated Cortisol Levels

For patients with confirmed hypercortisolism, initiate osilodrostat at 2 mg twice daily as first-line medical therapy, titrating by 1-2 mg every 2 weeks based on 24-hour urinary free cortisol levels, with a target mean serum cortisol of 150-300 nmol/L. 1, 2

Initial Diagnostic Confirmation

Before initiating treatment, you must:

• Exclude exogenous glucocorticoid use as the primary cause 3, 4
• Measure ACTH levels to differentiate ACTH-dependent (pituitary/ectopic, 80-85% of cases) from ACTH-independent (adrenal, 15-20% of cases) hypercortisolism 3, 5
• Obtain baseline ECG and correct hypokalemia/hypomagnesemia before starting medical therapy 1
• Perform pituitary MRI for ACTH-dependent cases or adrenal imaging for ACTH-independent cases 6, 5

Treatment Algorithm by Clinical Scenario

For Cushing's Disease (Pituitary Source)

Surgical candidates:

• Transsphenoidal surgery remains first-line treatment with remission rates of 37-88% 6, 7
• Consider preoperative medical therapy with adrenal steroidogenesis inhibitors only if surgery is delayed >2-3 months or in severely ill patients with life-threatening metabolic, psychiatric, infectious, or cardiovascular/thromboembolic complications 8

Medical therapy (post-surgical failure or non-surgical candidates):

• Osilodrostat is the most effective agent based on prospective trials, starting at 2 mg twice daily, titrating every 2 weeks up to maximum 30 mg twice daily 8, 1
• Osilodrostat works within hours and does not cause hypogonadism in men, unlike ketoconazole 7
• Alternative agents include ketoconazole (400-1200 mg/day, works within days) or metyrapone (works within hours) 8, 6, 7
• For mild disease with visible tumor, cabergoline may be considered but is less effective 7

For Adrenal Source

• Laparoscopic adrenalectomy for benign adenomas 6, 7
• Open adrenalectomy with lymph node removal for suspected carcinomas 6, 7

For Ectopic ACTH Source

• Surgical removal of ectopic tumor is first-line 6, 7
• If surgery not possible: medical therapy or bilateral adrenalectomy 6, 7

Monitoring During Medical Therapy

Biochemical monitoring:

• Measure 24-hour urinary free cortisol every 1-2 weeks during titration until stable 1
• Target mean serum cortisol of 150-300 nmol/L through the day 2
• Once maintenance dose achieved, monitor cortisol at least every 1-2 months 1
• UFC is not useful for diagnosing adrenal insufficiency; use morning cortisol instead 8

Clinical monitoring:

• Assess weight, blood pressure, glycemia, and quality of life at each visit 8
• Repeat ECG within one week after treatment initiation 1
• Monitor ACTH levels with adrenal-targeting agents, as significant elevations may indicate tumor growth requiring MRI 8
• Perform MRI 6-12 months after initiating treatment, then every few years 8

Safety monitoring:

• Watch for adrenal insufficiency symptoms (fatigue, nausea, hypotension) 1
• Monitor liver function tests regularly with ketoconazole, though mild stable elevations don't require discontinuation 8
• Check for QTc prolongation, especially with combination therapy 8

When to Escalate or Switch Therapy

Change treatment if cortisol levels remain persistently elevated after 2-3 months on maximum tolerated doses. 8

Combination therapy approach:

• If cortisol decreases but doesn't normalize, or there's partial clinical improvement, add a second agent rather than switching 8
• Combine ketoconazole with metyrapone or osilodrostat to maximize adrenal blockade 8
• For visible tumors, combine ketoconazole or pasireotide with cabergoline 8
• Monitor for overlapping toxicities, particularly QTc prolongation 8

Switch to different monotherapy if:

• Clear resistance despite dose escalation 8
• Ensure under-dosing isn't misinterpreted as resistance 8

Bilateral Adrenalectomy as Last Resort

Consider bilateral adrenalectomy when medical therapy fails to control severe hypercortisolism 6, 7

Benefits:

• Provides immediate cortisol control 6
• Long-term improvement in BMI, diabetes, hypertension, and muscle weakness in >80% of patients 6, 7

Consequences:

• Requires lifelong glucocorticoid and mineralocorticoid replacement 6, 7
• Monitor plasma ACTH and perform serial pituitary imaging starting 6 months post-surgery 6
• Long-term relapse due to adrenal rest stimulation is uncommon (<10%) 6

Critical Pitfalls to Avoid

• Do not under-dose ketoconazole due to fear of hepatotoxicity; it is often under-dosed, limiting efficacy 8
• Do not use UFC to diagnose adrenal insufficiency during treatment; it is not sensitive for this purpose 8
• Do not stop adrenal-targeting agents immediately if tumor growth is seen; first determine if it's due to loss of feedback or aggressive disease behavior 8
• Do not use preoperative medical therapy routinely; it may make postoperative remission assessment difficult if HPA axis recovers 8
• Avoid glucocorticoid over-replacement with block-and-replace regimens to prevent iatrogenic Cushing's syndrome 8

Special Populations

Hepatic impairment:

• Moderate (Child-Pugh B): Start osilodrostat at 1 mg twice daily 1
• Severe (Child-Pugh C): Start osilodrostat at 1 mg once daily in evening 1
• Require more frequent monitoring during titration 1

Renal impairment:

• No dose adjustment needed, but use caution interpreting UFC due to reduced excretion 1